Title
Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE
GSBS Program
Interdisciplinary Graduate Program
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology
Date
5-1-2007
Document Type
Article
Medical Subject Headings
Animals; Antigen-Antibody Complex; Antigens, Neoplasm; B-Lymphocytes; CpG Islands; DNA-Binding Proteins; Dendritic Cells; HMGB1 Protein; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Oligodeoxyribonucleotides; Receptors, Cell Surface; Toll-Like Receptor 9
Disciplines
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
Abstract
Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.
Rights and Permissions
Citation: Nature Immunology 8, 487 - 496 (2007). doi:10.1038/ni1457